The manner in which chemicals or drugs are administered has gained increasing attention in the past two decades. Normally, a chemical is administered in a high dose at a given time only to have to repeat that dose several hours or days later. This is not economical and sometimes results in damaging side effects. As a consequence, increasing attention has been focused on methods of giving drugs continually for prolonged time periods and in a controlled fashion. Controlled or sustained release dosage forms provide a therapeutic dose of the drug soon after administration, and then gradually release the drug over an extended period of time. The primary method of accomplishing this controlled release has been through incorporating the drugs within polymers or to surround or encapsulate a core comprising the drug with a polymer coat. Depending on the type and amount of drug, as well as the type and amount of polymer and other pharmaceutically acceptable excipients the desired controlled release profile can be obtained.
The majority of polymers used to develop coatings for controlled release dosage forms are hydrophobic and can be applied either dry, from a solution, or suspension. As most of these polymers are poorly soluble in water, they are usually applied by dissolving the polymer in an organic solvent and then sprayed onto the drug core and evaporating off the solvent. The use of organic solvents, however, is considered problematic for several reasons. The most obvious reason relates to the safety hazards associated with the use of organic solvents. Organic solvents in general are highly flammable and carcinogenic. Further, organic solvents are expensive and the storage, disposal and use of organic solvents raise environmental concerns. Accordingly, it would be desirable to prepare aqueous suspensions or solutions of controlled release coatings comprising hydrophobic polymers suitable for coating a wide variety of drug cores.
Eudragit® NE30D, which contains 30% solids, is one of the first aqueous polymeric dispersions used for coating pharmaceutical dosage forms. Eudragit® NE30D has many advantages over other polymers for use as a film former for obtaining a controlled release drug profile and is thus ideally suited for controlled or sustained release drug formulations. The polymer forms a soft, flexible film at room temperature without any plasticizer. Also, no reactions or absorptive effects are observed when the polymer comes in direct contact with a therapeutically active agent. It is prepared by emulsion polymerization and consists of neutral copolymers of ethyl acrylate-methyl methacylate esters that are insoluble over the entire physiological pH range but will still swell in water and give permeable membranes. The permeability is independent of pH and is thus suitable for the development of pH-independent modified-release oral dosage forms, provided that the solubility of the drug is also pH-independent.
One of the most significant differences between aqueous polymeric solutions and dispersions is the role water plays during film formation. In solutions, water is a solvent and drying is accompanied by an excessive increase in viscosity, which in turn suppresses the rate of evaporation. Excess energy is therefore required to drive off the water. In contrast, in polymeric dispersions such as Eudragit® NE30D, water is only a dispersion medium and does not solvate the polymers. Consequently, less heat is needed to evaporate the water. Fast water evaporation coupled with the high solids content of the dispersion significantly reduces processing time. These properties are especially critical when dealing with highly water-soluble or moisture sensitive therapeutically active agents.
The pigment binding capacity of Eudragit® NE30D is very high, so that up to ˜2-3 parts by weight of additives can be incorporated into 1 part by weight of dry polymer without affecting the film properties. The polymer is also compatible with a wide variety of pharmaceutical excipients.
Plasticizers are generally added to coating formulations to modify the physical properties i.e., the glass transition temperature (Tg) of the polymer to make it more usable. The Tg is the temperature at which an amorphous polymer (or the amorphous regions in a partially crystalline polymer) changes from a hard and relatively brittle condition to a viscous or rubbery condition. Plasticizers function by decreasing the Tg of the polymer so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical stress. Eudragit® NE30D, however, has a low Tg and accordingly does not require the use of plasticizers. In fact, addition of plasticizers can be detrimental as it can increase the viscosity of the Eudragit® NE30D formulation and negate one of the distinct advantages of the dispersion over the polymeric solution. Incorporation of plasticizers into Eudragit® NE30D formulations can also increase the tackiness of the coat and complicate the coating process (Ghebre-Sellassie and Nesbit. Application of Eudragit E30D in Controlled-Release Coatings in Aqueous Polymeric Coatings for Pharmaceutical Forms, J. McGinity Ed., 1989, Marcel Dekker, Inc., pp 247-266).
Due to its low Tg, Eudragit® NE30D is sensitive to excessive drying conditions or exposure to high temperatures. Ghebre-Sellassie and Nesbit (Application of Eudragit E30D in Controlled-Release Coatings in Aqueous Polymeric Coatings for Pharmaceutical Forms, J. McGinity Ed., 1989, Marcel Dekker, Inc., pp 247-266) state that excessive drying of Eudragit® NE30D coats can be detrimental as such conditions do not allow the coating formulation to spread out evenly and promote particle deformation and coalescence. Also, during the coating process, the product temperature should be kept at around 26° C. If the product temperature is very high, the coating material becomes tacky owing to the low Tg of Eudragit® NE30D, which leads to agglomeration of the coated product. Ghebre-Sellassie and Nesbit also emphasize that Eudragit® NE30D coated products should not be stored at temperatures above 40° C., as stability tests conducted at elevated temperatures may not correlate with the long-term behavior of Eudragit® NE30D coated products at room temperature.
Attempts have been made in the prior art to design microporous aqueous polymer coatings suitable for use on drug cores to obtain controlled or sustained release profiles using the Eudragits, and in particular Eudragit® NE30D. U.S. Pat. No. 5,529,791 for example, teaches controlled release dosage forms of Diltiazem in which the Diltiazem drug core is surrounded by a water-soluble and/or dispersible film forming polymer or copolymer constituting the microporous membrane. The polymers or copolymers taught include the polyacrylates and polymethacrylates of the Eudragit type, such as Eudragit NE30D, L30D, and RS30 D, ethylcelluloses, hydroxypropyl cellulose and hydroxypropylmethylcellulose and their derivatives. In addition to the polymer or copolymer, the microporous membrane contains, preferably, talc and/or magnesium stearate as a lubricant, polyvinylpyrrolidone as a plasticizer, titanium dioxide as a pigment, Tween 80 as an emulsifier, and silicone oil as an antifoaming agent. Other plasticizers taught include triacetin, dibutylpthalate, dibutylsebacate, citric acid esters, polyethyleneglycols, and polypropyleneglycols. The Eudragit® NE30D coated beads were cured for 16 hours at 50° C. (Example 3) or for 15 hours at 45° C., 5-10° C. beyond the recommended temperature for Eudragit® NE30D. Further, long-term stabilization data was not presented for the coated products, and accordingly, it is not known what effect the elevated temperature had, if any, on the stability of the controlled release dosage form of Diltiazem.
U.S. Pat. No. 5,286,493 is directed to stabilized controlled release formulations having an aqueous acrylic polymer coating. The '493 patent also teaches the use of controlled release coatings covering a solid dosage form. The coating is derived from aqueous dispersions of an acrylic resin, which provides a substantially stable release pattern of a drug from the dosage form. The acrylic resins taught are the ammonio methacrylate co-polymers as for example Eudragit® RL30D, RS30D and combinations thereof. The acrylic coatings include an effective amount of a suitable plasticizing agent. The stable Eudragit® RL30D and/or RS30D coated products are cured at temperatures above the Tg of the acrylic polymers. The '493 patent does not teach the use of Eudragit® NE30D.
U.S. Pat. No. 5,478,573 teaches delayed, sustained-release propranolol pharmaceutical preparations purportedly achieved by surrounding a water-soluble drug core with a hydratable diffusion barrier which delays drug release by for about 2-10 hours. The hydratable diffusion barrier is said to comprise a film-forming polymer such as acrylic resin or ethyl cellulose or mixtures thereof and an additive which con trolls the rate of hydration and permeability of the diffusion barrier. The preferred insoluble film-forming polymers are aqueous dispersions of fully esterified acrylic resins such as Eudragit® NE30D. The additives controlling the rate of hydration and permeability of the diffusion barrier are preferably selected from the group consisting of fully esterified acryclic resins containing quaternary amine side chains, anionic surfactants, lubricants, plasticizers, inert water soluble materials and mixtures thereof. The '573 patent teaches that the drug beads coated with the aqueous polymeric dispersion are dried at 35° C. to 60° C. for 8 hours to 5 days. No data is presented on the long-term stability of the products.
Another controlled release pharmaceutical dosage form using an aqueous acrylic polymer dispersion is taught in U.S. Pat. No. 5,871,776. The controlled release profile is obtained, however, using multiple layers of films. The outermost layer is comprised of the aqueous acrylic polymer dispersion. The preferred acrylic polymer is Eudragit® NE30D. The coatings may also contain other pharmaceutically acceptable excipients such as fillers, anti-adherents, pharmaceutically acceptable pigments and lubricants/glidants. The coated drug pellets are cured at a temperature in the range of from about 30° C. to about 50° C., preferably from about 35° C. to about 45° C. and most preferably about 40° C. for a period of about 5 to about 10 days, an preferably about 7 days. The inventors surprisingly found that in contrast to the preferred short curing times taught in the prior art, long curing times help stabilize the release of the drug from the coated pellets after long storage periods.
International Patent Publication No. WO 02/058677 describes a film coating composition comprising an aqueous acrylic polymer dispersion, a surfactant, and sodium stearyl fumarate. The acrylic polymer dispersion is preferably Eudragit® NE30D. There does not appear to be any teaching as to the curing temperature and furthermore no data is presented with regard to long-term stability of the coated product.
In summary, it would seem that although the prior art teaches the use of aqueous acrylic dispersion coatings of Eudragit® NE30D, in most part, the prior art does not seem to have overcome long term stability problems of products coated with aqueous Eudragit® NE30D dispersions. Where the products have been found to be stable, the length of curing is very long and this is inefficient to the manufacturing process and also raises problems with storage of scale-up product. Accordingly, and given the advantages and versatility of Eudragit® NE30D, it would desirable that a stable controlled or sustained release coat be developed with short curing times to enhance process times. It is therefore an object of this invention to develop such a product.